4-oxa steroids and process



United States Patent 3,499,913 4-OXA STEROIDS AND PROCESS Robert Joly, Montmorency, Julien Warnant, Neuilly-sur- Seine, and Jean Jolly, Clichy-sous-Bois, France, assignors to Roussel-UCLAF, Paris, France, a corporation of France No Drawing Filed Jan. 3, 1968, Ser. No. 695,364 Claims priority, application France, Jan. 6, 1967, 90,264, 90,265 Int. Cl. C07d 101/00; C07c 167/02, 169/10 US. Cl. 260-345.2 25 Claims ABSTRACT OF THE DISCLOSURE '1 his invention relates to a 4-oxa steroid of the formula Riv Ire/Kl where R and R represent lower alkyl, R" and R' represent a member selected from the group consisting of hydrogen, a-lower alkyl and ,B-lower alkyl, R and R" represent a member selected from the group consisting of hydrogen, a-rnethyl and fi-metyhl, Y represents a member selected from the group consisting of O,

OR COOHz and Rvii Rviii CLAIM OF PRIORITY The right of priority under 35 USC 119 is hereby claimed, based on the corresponding French patent applications P.V. 90,264 and RV. 90,265, both filed Jan. 6, 1967, on our behalf.

THE PRIOR ART 3 alkoxy l9-nor-3-methyl-4 oxa-A -[9fl]-androstene-l7B-ol and its derivatives in the 17 position have previously been reported in French Patent 1,366,725. However, these compounds are not suitable for the preparation of steroid compounds of natural configuration due to the inverted configuration on the 9 carbon atom. Moreover, they are prepared by a diiferent method.

OBJECTS OF THE INVENTION An object of the invention is the .obtention of a 4-oxa steroid intermediate having a stable A ring useful in steroid synthesis for the further reactions on the C and D rings.

Another object of the invention is the obtention of a 4-oxa steroid .of the formula wherein R and R represent lower alkyl, R" and R' represent a member selected from the group consisting of hydrogen, a-lower alkyl and ,B-lower alkyl, R and R represent a member selected from the group consisting of hydrogen, a-methyl and fl-methyl, Y represents a member selected from the group consisting of O,

ORvi OOCHa and wherein R represents lower alkyl, R" and R' represent a member selected from the group consisting of hydrogen, a-lower alkyl and ,B-lower alkyl, R and R represent a member selected from the group consisting of hydrogen, tat-methyl and fl-methyl, Y represents a member selected from the group consisting of O,

OR" COOH;

and vii Rviii wherein R" represents a member selected from the group consisting of hydrogen, lower alkyl and the acyl of an organic carboxylic acid having 1 to 7 carbon atoms, R represents a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl and lower haloalkynyl, and R" represents a member methyl, with a lower alkyl orthoformiate of the formula HC(OR') wherein R represents lower alkyl, in the presence of an acid agent and recovering said 4-oxa steroid.

A yet further object of the invention is the development of processes for the obtention of known steroids through the intermediary of the above 4-oxa steroid.

These and other objects of the present invention will become more apparent as the description thereof proceeds.

DESCRIPTION OF THE INVENTION These objects have now been achieved in the discovery of novel 4-oxa steroids of the general Formula I:

wherein here and thereafter.

R is a lower alkyl radical,

R is a lower alkyl radical,

R" is a lower alkyl radical or a hydrogen atom, R is a lower alkyl radical or a hydrogen atom, R is the methyl radical or a hydrogen atom, R is the methyl radical or a hydrogen atom,

Y is one of the groupings:

OH lower acyl COCHH COCH 0 lower alkyl 0,

H H H 01-1 11 ORvi lower saturated or unsaturated, substituted or unsubstituted hydrocarbon,

R" being selected from the group consisting of a hydrogen atom, a lower alkyl radical and a lower acyl radical.

The substituents R", R', R and R can be in the alpha or beta configuration. The lower acyl can be the acyl of an organic carboxylic acid having 1 to 7 carbon atoms and particularly benzoyl and lower alkanoyl such as acetoxy.

More particularly the 4-oxa steroids of the invention are those steroids of the general Formula I, wherein R is a lower alkyl radical comprising from 1 to 4 carbon atoms, R is a lower alkyl radical comprising 1 or 2 carbon atoms, R" is a hydrogen atom or a methyl, R' is a hydrogen atom or a methyl, R is a hydrogen atom or a methyl, R is a hydrogen atom or a methyl. Preferred are the 4- oxa steroids of the formula A? A U wherein R is lower alkyl and especially methyl, ethyl, propyl or butyl, R is lower alkyl and especially methyl or ethyl, and Z is O,

OH 0 lower acyl C 0 CH3 t and s The novel compounds of Formula I are valuable intermediates for the preparation of steroid derivatives. They have an advantage in that they practically do not exhibit any reactive function at the level of the A ring at the time of certain substitutions or conversions at the level of the C and D rings, which will be described later on. These compounds of Formula I have a good stability in alkaline medium. However, the opening of their pyranic ring is easily effected in acid medium with formation of the corresponding 4,5-seco-3,5-diketonic derivatives, the cyclisation of which, when performed according to the described methods, allows the A ring to be completed in normal steroid configuration.

Some 4-oxa-steroids are already known (see for example the French Patent 1,366,725).

However, these compounds are not suitable for the preparation of steroid compounds of natural configuration, due to the inversion of configuration which they exhibited at the level of the carbon in the 9 position as discussed above. Moreover, they were prepared according to a method (the catalytic hydrogenation in an acid medium of 3,5-dioxo-4,5-seco-A steroids in the presence of a lower aliphatic alcohol, the latter determining the nature of the 3-alkoxy grouping of the formed pyranic derivative), which was entirely difierent to that used to obtain the compounds of Formula I.

Now, it has been found, and the process of the invention is based thereon, that 4,5-seco-3,5-diketonic steroid derivatives having a 9, 10 double bond, when reacted with a lower alkyl ortho-formiate, in the presence of an acid agent, provided the derivatives with pyranic structure of Formula I and that the reaction proceeds gently and gives satisfactory yields.

Thus, the compounds of the general Formula I offer another advantage in that their access is easy, whereas, as has previously been reported, a 1,5-dione reacted in either an acid medium or in an alkaline medium gives rise generally to the formation of a cyclohexenic ring having a conjugated ketone function.

The process for the preparation of the 4-oxa steroids of Formula I comprises the reaction of a 3,5-dioxo-4,5- sew-A steroid of the general Formula II ill RV Cl with a lower alkyl orthoformiate of the general Formula III in the presence of an acid agent and the desired compound is isolated.

Preferably, the lower alkyl orthoformiate used in the process of the invention is methyl or ethyl orthoformiate and the reaction is conducted in the presence of a catalytic amount of a strong acid, such as para-toluene sulfonic acid, methane sulfonic acid, perchloric acid, or sulfuric acid. The choice of the orthoformiate determines the nature of the alkoxy grouping of the resulting pyranic derivative. Thus, methyl ortho formiate leads to the methoxy-pyranic derivative, whereas ethyl orthoformiate provides the corresponding ethoxylated compound. The condensation with orthoformiate is preferably effected in a polar organic solvent such as methanol, ethanol or dioxane, and it occurs quickly at temperatures approximating room temperature.

As is mentioned above, the novel 4-oxa steroids of the general Formula I are valuable intermediates for the preparation of steroid derivatives. The ketonic functions in the 3 and 5 positions are protected and do not undergo reaction while substitutions are made on the C and D rings. This has led to a general and unobvious method of producing the said steroids.

For example, it has been ascertained, that the 4-oxa steroids of the general Formula I are easily suitable for the introduction, by bromination and dehydrobromination, of the 11, 12 double bond, so as to give thus, after closing the A ring, a 4,9,11-triene steroid. They are also suitable for the introduction of a substituent in the 17m position, so as to prepare monoene, diene or triene steroids alkylated, ethynylated, etc., in this position.

A few cases of utilization of these compounds of Formula I in the synthesis of physiologically active derivatives are described hereinafter. It is evident that this utilization is a part of the present invention.

A preferred use of a compound of the Formula I consists in preparing 17/3-benzoyloxy-4,5-seco-A -estra-diene-3,5-dione. To obtain this compound, a 3-methyl-3- alkoxy-4-oxa-17/3-benzoyloxy-A estradiene is selectively brominated in the 11 position. The ll-bromo- 17B-benzoyloxy-4,5-seco-A -estrene3,5-dione formed is dehydrobrominated and the desired 17/3-benzoyloXy-4,5 seco-A -estradiene-3,5-dione is obtained. This compound is then cyclised in alkaline medium, according to the French Patent 1,380,414 so as to form 17/3-benzoyloxy-A estratriene 3 one, which is endowed with a high anabolising and androgenic activity.

The 3 methyl 3 alkoxy 4 oxa 17/8 benzoyloxy-A -estradiene used is preferably the 3-ethoxylated derivative.

Bromine is advantageously used to effect the selective bromination in the 11 position of 3 methyl 3 ethoxy-4- oxa-l7fl-benzoyloxy-A -estradiene, and it is convenient to operate in a polar organic solvent, such as dimethylformamide, in the presence of a basic agent, such as alkali metal acetate. The further dehydrobromination of the ll-brominated derivative is conveniently effected in the presence of a basic agent, such as lithium carbonate and of a lithium halide, such as the bromide. The reaction is conducted in a polar organic solvent, such as dimethylformamide.

Another important use of a compound of the Formula I is the preparation of 17ot-ethynyl 4,4-seco A estrene 17B-ol-3,5-dione. For this purpose, an ethynylation agent is reacted in basic medium with a 3-methyl-3- alkoxy 4 -oxa-A -estradiene 17 one. The 3- methyl-3-alk-oxy 4 oxa 17a-ethynyl-A -estra diene 17B-ol-formed is hydrolysed in aqueous acid medium to obtain 17a-ethynyl 4,5 seco-A -estrene-17fiol-3,5-dione.

This compound is easily converted into 17a-ethynyl- A -estradiene 17,8-ol-3-one by applying the process described in the French Patent 1,497,593. This process involves reacting the compound with a basic cylisation agent in anhydrous medium or an acid cyclisation agent in the presence of a small amount of water.

From the 17u-ethynyl A -estradiene-17B-QI-3 one prepared in this way, there is obtained, according to the process of US Patent 3,136,790, l7a-ethynyl- A -estrene-17B ol 3 one, which is a well known progestative agent.

The 3 methyl 3 alkoxy 4 oxa-A -estradiene-17-one used is preferably the 3 ethoxylated deriva tive.

To ethynylate the 3 methyl 3 ethoxy 4 oxa- A -estradiene 17 one, an alkali metal acetylide in an aprotic medium (for example tol-uene or benzene) may be conveniently used. The subsequent hydrolysis 1s advantageously effected in aqueous medium with a strong acid, such as hydrochloric acid and in a polar solvent or a mixture of polar solvents.

Another important use of a compound having the Formula I consists in preparing 13fi-ethyl-17a-ethynyl- A -gonadiene 17,6-ol-3-one. For the preparation of this compound, an ethynylation agent is reacted, in basic medium, with a 3 methyl-3-alkoxy-4-oxa l3fi-ethyl- A -gonadiene-17-one. The 3 methyl 3 alkoxy- 4-oxa-l3,8 ethyl 17ot-ethynyl-A -gonadiene-UB- 01 formed is hydrolysed in acid medium and there is obtained 13B-et'nyl-17a-ethynyl 4,5 seco-A -gonene-17 3- 3,5-dione.

This compound is easily converted into 13,8-ethyl 17aethynyl-A -gonadiene 17/3-ol-3-one by applying the process described in the French Patent 1,497,593. This process involves reacting the compound with a basic cylisation agent in anhydrous medium or an acid cyclisation agent, in the presence of a small amount of water.

Starting from the thus prepared 1-3B-ethyl-17a-ethyny1- A gonadiene 17,8-ol-3-one and by applying the process of the US. Patent 3,136,790, 13;8ethyl-'17a-ethynyl- A -gonene 175 01 3 one, which is a Very active progestomimetic agent, is easily obtained.

The 3 methyl 3 alkoxy 4 oxa 13fi-ethyl- A -gonadiene 17 one, preferably used, is the 3-ethoxylated derivative.

The ethynylation of 3 methyl 3 ethoxy 4 oxa- 13B-ethyl A -gonadiene 17 one and the further hydrolysis of the formed ethynylated derivative are effected in an analogous way to that described above in the case of the corresponding 13;? methylated derivative.

Another important use of a compound of the general Formula I is in the preparation of 13,6-ethyl-A gona triene 3,17 dione.

This product is a valuable intermediate in the synthesis of 4,9,11-gonatriene derivatives and this is particularly useful for the preparation of 13fl-ethyl 17u-ethynyl- A -gonatriene-17fl-ol-3-one, which is a strongly active progestomimetic agent (see the Belgian Patent 679,368).

Until now, to obtain this compound, 13fl-ethyl-4,5- S6C0-A -gOnene 17B ol 3,5-dione was cyclised into -ethyl A -gonadiene -ol-3-one, then after a previous protection of the ketone in the 3 position in the form of ketal, the alcohol in the 17 position was oxidized into a ketone, and, at the end of the process, the 11,12 double bond was introduced. See Belgian Patents 657,260 and 674,178 as well as US. patent application S.N. 517,061, filed Dec. 28, 1965, now Pat. No. 3,453,267.

Now, it has been found in the preparation of l3r3-ethyl- A -gonatriene-3,17-dione, that it is advantageous to start from a 3-rnethyl 3 alkoxy 4 oxa-13fi-ethyl- A -gonadiene 17 one, which is selectively brominated in the 11 position with a bromination agent, and to dehydrobrominate the ll-bromo l3fl-ethyl-4,5- seco-A -gonene 3,5,17 trione by the action of a basic agent, 13-p-ethyl-4,5-seco-A gonadiene 3,5,17 trione is obtained, which is cyclised by acting an alkaline agent in anhydrous medium and the desired 13B-ethyl-A gonatriene 3,17-dione is isolated.

The selected bromination in the 11 position of 3-methyl- 3-a1koxy 4 oxa 13p ethyl A 1 -gonadiene- 17-one is effected by the action of Nl-bromosuccinimide and the reaction is conducted in a polar organic solvent, such as formamide or dimethylforrnamide.

The dehydrobromination of the ll-brominated derivative'is advantageously effected in situ without isolating intermediately the brominated derivative from the reaction medium. The basic agent used to effect this dehydrobromination, is preferably lithium carbonate and it is advantageous to operate in the presence of a lithium halide, such as the chloride or bromide and in a polar organic solvent, such as formamide or dimethylformamide. When the dehydrobromination is effected in situ, it is convenient to proceed in the same solvent as that used for the bromination.

The alkaline agent used to effect the cyclisation of the A ring of 13fl-ethyl-4,5-seco-A -gonadiene-3,5,17-trione is, for example, an alkali metal lower alkanolate or an alkali metal hydroxide and the reaction is conducted in an anhydrous medium. The actually preferred cyclisation agent is potassium hydroxide, which is used in a methanolic medium, but it is evident that other alkaline agents, such as caustic soda or an alkali metal lower alkanolate may also be suitable.

The following examples illustrate the invention both for the preparation of the pyranic alkoXy derivatives as for the applications of these derivatives for the preparation of physiologically active compounds. These examples, however, are not deemed to give to the invention any limitative character.

Examples of the preparation of compounds of Formula I 1.Preparation of 3-methyl-3-ethoxy-4-oxa' l7fi-benzoyloxy-A -estradiene 20 gm. of 175-benzoyloxy-4,5-seco-A -estrene-3,5-dione, a product described in French Patent No. 1,364,556 and in United States Patent No. 3,101,354, are introduced into 20 cc. of ethanol under an atmosphere of nitrogen. 0.005 gm. of para-toluene sulfonic acid is added. The mixture is stirred for 15 minutes at room temperature and 16 cc. of ethyl orthoformiate are introduced. The agitation is maintained for 2 hours at room temperature. Then the pH of the reaction medium is brought to 8.0 by adding triethylamine. The reaction mixture is poured into water and extracted with methylene chloride. The methylene chloride extracts are combined. The obtained organic solution is washed with water, dried and concentrated to dryness under reduced pressure and under an atmosphere of nitrogen to obtain 25.6 gm. of crude 3 methyl 3 ethoxy-4-oxa-l7fl-benzoyloxy-A estradiene, containing ethyl orthoformiate.

As far as is known, this product is not described in the literature.

Example Example 2.Preparation of 3-methyl-3-methoxy-4-oxa- A -estradiene-l7-one 4 gm. of 4,5-seco-A -estrene-3,5,17-trione, a product described in French Patent No. 1,305.992. then 2.85 cc. of methyl orthoformiate are introduced into 4 cc. of methanol under an atmosphere of nitrogen. The mixture is agitated for 15 minutes at a temperature between and C. 0.001 gm. of paratoluene sulfonic acid is then introduced and the agitation is maintained for hours at a temperature between 0 and +5 C. The temperature of the reaction medium is brought to C. and agitation is continued for 2 hours at this temperature. The pH of the reaction medium is then brought to 8.0 by adding triethylamine. The whole is poured into Water, extracted with methylene chloride and the isolation is completed as in the preceding example.

Accordingly, 3 methyl 3 methoxy-4-oxa-A estradiene-l7-one is obtained.

As far as is known, this product is not described in the literature.

Example 3.Preparation of 3-methyl-3-ethoxy-4-oxa- A -estradiene-17-0ne 30 gm. of 4,5-seco-A -estrene-3,5,17-trione, a product described in French Patent No. 1,305,992, then 36 cc. of ethyl orthoformiate are introduced into 30 cc. of ethanol under an atmosphere of nitrogen. This mixture is agitated for 15 minutes between 0 and +5 C. 0.0075 gm. of para-toluene sulfonic acid is then introduced and the agitation is maintained for 16 hours at a temperature between 0 and +5 C. Thereafter, the temperature of the reaction mixture is brought to +20, C. and main tained for 2 hours. The pH of the reaction medium is brought to 8.0 by adding triethylamine and the whole is poured into water and agitated for 15 minutes at room temperature. The aqueous mixture is extracted with methylene chloride, and the methylene chloride extracts are combined. The obtained solution is washed with water and dried. To this methylene chloride solution, gm. of magnesium silicate are added while agitating. The mag nesium silicate is filtered off and the solution is concentrated to dryness under reduced pressure under an atmosphere of nitrogen to obtain 35.4 gm. of crude 3-methyl 3-ethoxy-4-oxa-A -estradiene-l7-one, containing a small amount of ethyl orthoformiate.

N.M.R. spectrum:

Methyl in 13 positionat 54 hz. Methyl of ethoxy groupingtriplet at 606773.5 hZ. Methyl in the 3 positionat 86 hz. Methyl of ethoxy grouping-quadruplet at 2032l0 2l7226 hz.

As far as is known, this product is not described in the literature.

Example 4.Preparation of 3-methyl-3-ethoxy-4-oxal3;8-ethyl-A -gonadiene-17-one 11.6 gm. of 13fl-ethyl-4,5 seco A gonene-3,5,17- trione are introduced at a temperature between 0 and +5 C. into a mixture of 11.6 cc. of ethanol and 13.8 cc. of ethyl orthoformiate. The mixture is agitated for 15 minutes. Then 2.8 mg. of para-toluene sulfonic acid are added. The agitation is maintained for 15 hours at a temperature between 0 and +5 C. under an atmosphere of nitrogen. The temperature of the reaction medium is brought to 20 C. and the whole is agitated for one hour at 20 C. The pH of the reaction medium is brought to 8.0 by adding triethylamine. Water and methylene chloride are added and the mixture agitated. The organic phase is decanted oif. The aqueous phase is extracted with methylene chloride. The methylene chloride extracts are combined with the main organic phase. The obtained methylene chloride solution is washed with water, dried and concentrated to dryness under reduced pressure.

Thus, 13.4 gm. of 3-methyl 3 ethoxy-4-oxa-13 8- ethyl-A -gonadiene-17-one are obtained.

I. R. spectrum:

Presence of ketone in the 17 position Band at 1653 cm. corresponding to As far as is known, this product is not described in the literature.

The 13/3-ethyl 4,5 seco A -gonene-3,5,17-trione, used as starting material in the above example, is prepared in the following way:

A sulfochromic acid solution is prepared by dissolving 27.5 gm. of chromic acid in a mixture of 60.5 cc. of water and 20.6 cc. of an aqueous solution of 66 B. sulfuric acid. On the other hand, 106 gm. of crude 13,8-ethyl-4,5- seco A gonene 17fl-ol-3,5-dione, described in Belgian Patent No. 657,260 (an oily product obtained in paragraph 4 of stage F, after the acid hydrolysis, prior to the chromatography through magnesium silicate) are dissolved in 1,060 cc. of acetone, under an atmosphere of nitrogen. The solution is cooled to -10 C. and the previously prepared sulfochromic acid solution is introduced with agitation at 10 C. in about 15 minutes. The mixture is agitated for one hour at 10 C.; then a mixture of 53 cc. of an aqueous solution of 35 B. sodium bisulfite and 159 cc. of water is intrdduced at a temperature between 0 and +5 C. The mixture is agitated for 15 minutes at a temperature between 0 and +5 C. Acetone is distilled 01f under reduced pressure and water is added. The aqueous phase is extracted with methylene chloride. The extracts are combined and the obtained organic solution is washed with water, then with an aqueous solution of sodium bicarbonate, and finally with water.

The organic solution is dried, concentrated to dryness under reduced pressure to obtain 98 gm. of crude product. This crude product is chromatographed through magnesium silicate. By eluting with methylene chloride, there is obtained a fraction which, after triturating in an ethyl ether-isopropyl ether mixture provides a first yield of 27.5 gm. of crystals having a melting point of to 86 C. The elution is continued with methylene chloride containing 0.5% of methanol. The obtained solution is combined with the ethereal mother liquors of purification from the first yield and concentrated to dryness. The obtained residue is chromatographed through magnesium silicate and, first, eluted with a benzene-cyclohexane mixture (1 to 2) so as to eliminate an oily fraction, then with methylene chloride containing 1% of methanol to provide a second fraction, which, purified by triturating in ether, provides a second yield of 7.3 gm. of crystals having a melting point of 85 to 86 C. When the elution is continued with methylene chloride, a third fraction is obtained which, upon purification by crystallization from ether, provides a third yield of 13.66 gm. of crystals having a melting point of 85 to 86 C.

Accordingly, there are obtained, as a whole, 48.46 gm. of 13/3 ethyl 4,5 seco-A -gonene-3,5,17-trione, having a melting point of 85 to 86 C. and a specific rotation [a] =-|-2li1 (c.=1.l% in methanol).

U. V. Spectrum (ethanol): A max. at 248-249 mg As far as is known, this product is not described in the literature.

Example 5.-Preparation of 1,3 dimethyl 3 ethoxy- 4-oxa-17/3-acetoxy-A -estradlene Proceeding in the same manner as in Example 1, and starting from l-methyl 17,8 acetoxy-4,5-seco-A -estrene- 3,5 dione there is obtained l,3-dimethyl-3-ethoxy-4-oxa- 17fi-acet0xy-A -estradiene.

As far as is known, this product is not described in the literature.

The starting product, l-methyl 17B-acetoxy 4,5-secoA estrene 3,5-dione, may be prepared as follows: 19.71 gm. of l-acetoxy Z-methyl 4-pentanone are treated with 44 cc. of a 40% aqueous solution of hydrobromic acid. The mixture is heated to 125 C. and distilled over. The aqueous phase is extracted with ether and the ether distilled off. 14.3 gm. of l-bromo Z-methyl 4-pentanone are obtained which, upon treatment with ethylene-glycol in the presence of p-toluenesulfonic acid gives l-bromo 2-methy1 4,4- ethylene-dioxy pentane which appears in the form of a colorless liquid. Boiling point: 61 C. under 1.4 mm./Hg.

l-bromo 2-methyl 4,4-ethylenedioxy pentane, when submitted to the action of magnesium in tetrahydrofuran, gives a solution of the corresponding magnesium compound which is reacted With the 6-lactone of dextrorotatory 1,8-acetoxy 4-(2-carboxyethyl)-7a,;3-methyl 3am, 4B,7,7a-tetrahydroindane 5-01, described in US. patent application Ser. No. 361,872 filed Apr. 22, 1964, now Pat. No. 3,413,314. By applying the process described in this patent application l-methyl 17B-acetoxy-4,5-seco-A estrene 3,5-dione may be obtained.

Example 6.Preparation of 3,6a-dimethyl-3-ethoxy-4- oxa-17B-acetoxy-A -estradiene Proceeding in the same manner as in Example 1, and

starting from 6a-methyl-17/3-acetoxy-4,5-seco-A -estrener Proceeding in the same manner as in Example 3, and starting from 7ot-methyl-4,5-seco-A -estrene-3,5,17-trione, described in French Patent No. 1,456,779, there is obtained 3,7ot-dimethyl-3-ethoxy-4-oxa A5(1)19(11) estradiene-17-one.

As far as is known, this product is not described in the literature.

Example 8.Preparation of 2,3dimethyl-3-ethoxy-4-oxa- 17B-benz0yloxy-A -estradiene Proceeding in the same manner as in the Example 1, and starting from Z-methyl-17fi-benzoyloxy-4,5-seco-A estrene-3,5-dione, described in French Patent No. 1,284,- 566, there is obtained 2,3-dimethyl-3-ethoxy-4-oxa-l75- benzoyloxy-A -estradiene.

As far as is known, this product is not described in the literature.

Example 9. Preparation of 3-methyl-3-ethoxy-4-oxal3 3-propyl-A -gOnadiene 17-one Using the process described in Example IV but starting from 13{3-propyl-4,5-seco-A -gonene-3,5,17-tri0ne, 3-methyl-3-ethoxy-4-oxa-13fi-propyl-A gonadiene 17- one is obtained.

Infrared spectra:

Presence of 17 keto group Presence of a band at 1653 cm? corresponding to the group Presence of the As far as is known, this compound is not described in the literature.

The starting product, 13/3-propyl-4,5-seco-A -gonene-3, 5,17-trione is prepared using the process described in Example IV starting from 13fi-propyl-4,5seco-A -gonene- 17,8-ol-3,5-dione described in the Belgian Patent 657,260.

The 13 3-propyl-4,5-seco-A -g0nene-3,5,17-trione melts at 109 C.; [ix] =+31i2 (c. =0.5% in methanol).

As far as is known, this compound is not described in the literature.

EXAMPLES FOR THE USE OF COMPOUNDS OF FORMULA I Example 10.Preparation of 17B-benzoyloxy-4,5-seco- M -estradiene-3,5-dione Stage A.1l-bromo-17,8-benzoylbxy-4,5-seco A estrene-3,5-dione: 20 gm. of crude 3-methyl-3-ethoxy-4- oxa-17fibenzoyloxy A estradiene, described in Example 1, then 15.5 gm. of anhydrous sodium acetate are dissolved in 200 cc. of dimethylformamide under an inert atmosphere. 60 cc. of a 10% by weight solution of bromine in dimethylformamide are added over a period of about one hour with agitation. The agitation is then continued for 15 minutes at room temperature. The obtained suspension is poured into a water-ice-methylene chloride mixture. The suspension is stirred and the organic phase is decanted off. The aqueous phase is extracted with methylene chloride. The methylene chloride extracts are combined with the main organic solution. Then, the obtained organic solution is washed with water, then with an aqueous solution of sodium bicarbonate, and finally with water. The solution is dried and concentrated to dryness under reduced pressure, under an atmosphere of nitrogen. Isopropyl ether is added to the obtained residue. The formed precipitate is filtered with suction to obtain 25.6 gm. of crude 11-bromo-17fl-benzoyloxy-4,5- seco-A -estrene-3,S-dione, used as such for the next stage.

As far as is known, this product is not described in the literature.

Stage B.17fl-benzoyloxy-4,5-seco-A -estradiene-3,5- dione: 20 gm. of anhydrous lithium bromide and 20 gm. of lithium carbonate are introduced under inert atmosphere into 300 cc. of dimethylformarnide. The temperature of the reaction mixture is brought to C. and 25.65 gm. of crude 1l-bromo-l7,8-benzoyloxy-4,5-seco- A -estrene-3,5-dione, suspended in 39 cc. of dimethylformamide are introduced. The reaction medium is agitated for 18 hours under inert atmosphere. The temperature of the reaction mixture is then brought to 20 C. and, slowly, the mixture is poured into a water-ice-acetic acid mixture. Agitation is maintained for 30 minutes. Then the aqueous phase is extracted with methylene chloride. The methylene chloride extracts are combined. The combined organic solution is washed with water, then with an aqueous solution of sodium bicarbonate and finally with water. The solution is dried, and 40 gm. of magnesium silicate are slowly added thereto. Agitation is continued for 30 minutes. The magnesium silicate is then filtered off and the solution is concentrated to dryness under reduced pressure under at atmosphere of nitrogen. Sulfuric ether is added to the obtained residue. With agi tation, the temperature is maintained for 15 hours between C. and C. The formed precipitate is then filtered off with suction and dried to obtain 3.98 gm. of 17B-benzoyloxy 4,5 seco-A -estradiene-3,S-dione, having a melting point of 136 C. and a specific rotation [u] =-33i3 (c.:0.5% ethanol).

U.V. spectrum (ethanol): A max. 290 mp e=25,400.

This product, when admixed with 17,8-benzoy1oXy-4,5- seco-A -estradiene-3,5-dione, which is prepared according to the process described in French Patent No. 1,380,- 414, does not give a depression of the melting point.

By cyclization in an alkaline medium according to the process described in French Patent 1,380,414, 17,3-benzoyloxy-4,5-seco-A -estradiene 3,5 dione provides 176- benzoyloxy-A -estratriene-3-one, described in the said patent. This triene compound is endowed with a high anabolizing and androgenic activity.

Example 11.-Preparation of 17a-ethynyLA -estradiene- 17fl-ol-3-one State A.3-methyl-3-ethoxy-4-oxa-17a ethynyl-A -estradiene-l7fiZ-ol: Acetylene is bubbled for 2 hours 20 C. through 142 cc. of a solution of sodium tert.- amylate, containing 4.59 gm. of sodium per hundred cc. to form sodium acetylide. Thereafter, a solution of 30 gm. of crude 3 methyl-3-ethoxy-4-oxa-A -estradiene-17- one, described in Example 3, in 68 cc. of toluene is introduced. The mixture is agitated for 4 hours at room temperature while bubbling acetylene therethrough. Then, the reaction medium is brought to +10 C. and a solution of 30 gm. of ammonium chloride in 120 cc. of water is slowly introduced under an atmosphere of nitrogen. The whole is agitated for one hour at room temperature. The toluene is then eliminated under reduced pressure under an atmosphere of nitrogen. The aqueous phase is extracted with methylene chloride. The methylene chloride extracts are combined and the obtained organic solution is washed with water, dried, decolorized with animal charcoal, concentrated to dryness under reduced pressure under an atmosphere of nitrogen to obtain 34.6 gm. of crude 3-methyl-3-ethoxy-4-oxa-17a-ethynyl-A estradiene-17B-ol, used as such for the following stage.

As far as is known, this product is not described in the literature.

Stage B.17a-ethynyl-4,5-seco-A -estrene 17B-ol-3,5 dione: 20 gm. of crude 3-methy1-3-ethoxy-4-oxa-17aethynyl-M -estradiene-17fi-ol are dissolved in 120 cc. of acetone containing 20% of water by volume, under an atmosphere of nitrogen. 20 cc. of an aqueous solution of 2N hydrochloric acid are added and the solution is agitated for 2 /2 hours at room temperature. The pH of the reaction medium is then brought to 8.0 to 8.5 by adding an aqueous solution of sodium bicarbonate. The acetone is distilled olf under reduced pressure and the aqueous phase extracted with methylene chloride. The methylene chloride extracts are combined. The obtained organic solution is washed with water, dried, and 20 gm. of magnesium silicate are slowly added thereto, then filtered off. The obtained solution is concentrated to dryness under reduced pressure and under an atmosphere of nitrogen. The residue is admixed with sulfuric ether, taken to reflux for 15 minutes, cooled between 0 and +5 C. and filtered with suction to obtain 5.88 gm. of 17a-ethynyl- 4,5-seco-A -estrene-17 3-ol-3,5-dione having a melting point of 124 C. and a specific rotation [a] =73:2.5 (c.=0.6% in methanol).

U.5. spectrum (ethanol): A max at 248 to 249 m This product, admixed with 17ot-ethynyl-4,5-seco-A estrene-17fl-ol-3,5-dione, which is obtained according to the process described in French Patent 1,497,593, does not give any depression of the melting point.

Stage C.l7oc ethynyl A -estradiene-17/3-ol-3-one: 0.600 gm. of 17a-ethyny1-4,5-seco-A -estrene-17;3-ol-3,5- dione are introduced into 2.2 cc. of benzene under an inert atmosphere. Then, at temperatures between 0 C. and +3 C., and in 20 minutes, 1.4 cc. of a solution of sodium tert.-amylate in toluene, containing 2.45 gm. of sodium per hundred cc., are added thereto. The whole is agitated for 2 hours, while maintaining the temperature in the above-mentioned range. Thereafter one cc. of henzene, then a mixture of 0.3 cc. of tert.butyl alcohol and 0.5 cc. of benzene is added. The temperature is allowed to rise to 20 C. and the whole is agitated for one hour at this temperature. The pH is adjusted to 7 by adding a benzene solution of acetic acid. The mixture is agitated for 45 minutes and Water is then added. The solvents are eliminated under reduced pressure. The precipitate formed is filtered with suction, Washed and dried, to obtain 570 mg. of a product melting at 178 C.

This product is purified by crystallization from ethyl acetate to obtain 416 mg. of 17u-ethyl-A -estradiene- 17,8-01-3-one, having a melting point of 183 C. and a specific rotation [a] :355 (c.=0.2% in methanol).

U.V. spectrum (ethanol):

hmax. at 215 mp. 5:5,850 infi. 235236 mg 6=4,59O itrfl. 247 n'l,u 6 3,550

Amax. at 304 m e:20,000

This preparation of 17a-ethynyhA -estradiene-176-01- 3-one is described in French Patent 1,497,593.

From the thus prepared 17ot-ethynyl-A -estradiene- 17,8-ol-3-one, there is obtained, by applying the process which is described in US. Patent 3,136,790; 17u-ethynyl- .A -est1'ene-l7B-Ol-3-One, which is a well known progestative agent.

Example 12.Preparation of 13,8-ethyl-17u-ethynyl-A gonadiene-17B-ol-3-one Stage A.3-methyl-3-ethoxy-4-oxa-13/3-ethyl-17tx-ethynyl-A -gonadiene-17,8-ol: Acetylene is bubbled for 2 hours at room temperature through 61 cc. of a toluene solution of sodium tert.-amylate containing 2.7 gm. of sodium per hundred cc., so as to form sodium acetylide. A solution of 4 gm. of 3-methyl-3-ethoxy-4-oxa-13B- ethyl-A -gonadiene-17-one, prepared according to Example 4, in 8 cc. of toluene, is slowly introduced. The mixture is then agitated for 6 hours at room temperature while bubbling acetylene therethrough. The temperature of the reaction medium is brought to +10 C. and a solution of 4 gm. of ammonium chloride in 16 cc. of water is slowly introduced, without exceeding a temperature of +15 C. The solution is then agitated for 30 minutes under an atmosphere of nitrogen. Toluene is distilled off under reduced pressure and under an atmosphere of nitrogen. The aqueous phase is extracted with methylene chloride. The methylene chloride extracts are combined; the combined organic solution is washed with water, dried, decolorized with animal charcoal and concentrated to dryness under reduced pressure and under an atmosphere of nitrogen to obtain 4.21 gm. of crude 3 methyl 3 ethoxy 4 oxa 13B ethyl 17a ethynyl-N -gonadiene-17,8-01, used as such for the next stage.

As far as is known, this product is not described in the literature.

Stage B.13fi-ethyl-17a-ethynyl 4,5-seoo-A -gonene- 17 3-ol-3,5-dione: 0.6 gm. of crude 3-methyl-3-ethoxy-4- oxa-13fl-ethyl-17m-ethynyl-A -gonadiene-17,6-01 is dissolved in 3.6 cc. of acetone containing 20% of water by volume, under an atmosphere of nitrogen. 0.6 cc. of an aqueous solution of 2 N hydrochloric acid is added. The mixture is agitated for 4 hours at room temperature and, thereafter, the reaction mixture is slowly poured into water. Theaqueous phase is extracted with methylene chloride. The methylene chloride extracts are combined. The obtained organic solution is washed with water, then with an aqueous solution of sodium bicarbonate and finally with water. The solution is dried. 1.2 gm. of magnesium silicate is slowly added with agitation. The magnesium silicate is then filtered off and the solution is concentrated to dryness under reduced pressure and under an atmosphere of nitrogen. The residue is admixed with ethyl ether and cooled to to C. The precipitate formed is filtered with suction and dried to obtain 0.12 gm. of 1BB-ethyl-17u-ethynyl-4,5-seco-A -gonene-175-01- 3,5-dione, having a melting point of 128 to 129 C.

A sample of this product crystallized from ethyl ether has a melting point of 129-130 C. and a specific rotation [m] =-95:2 (c.=1% in methanol).

Analysis-Calculated for C H O (percent), molecular weight=328.43: C, 76.79; H, 8.59. Found (percent): C, 77.1; H, 8.9.

U.V. spectrum (ethanol): Amax. at 306 m infi. at 235 mu From the thus prepared 13flethyl-17a-ethynyl-A gonadiene-17p-ol-3-one, there is obtained, by applying the process which is described in US. Patent 3,136,790, 13/3-ethyl-17a-ethyny1-A -gonene-17B-0l-3-one, which is a very active progestomimetic agent.

Example 13.Preparation of 13B-ethyl-A -gonatriene- 3,17-dione Stage A.13fi-ethyl-4,5-seco-A" gonadiene 3,5,17- trione: 13.4 gm. of 3-methyl-3-ethoxy-4-oxa-13B-ethyl- A -gonadiene-17-one, described in Example 4, are dissolved in a mixture of 38 cc. of dimethylformamide and 0.8 cc. of water, under an inert atmosphere. Then, N-bromosuccinimide (about 6.4 gm.) is introduced at a temperature between 0 and +5 C., until obtention of a slight excess of bromine, which is detectable with starchpotassium iodide paper. The mixture is agitated for a further 15 minutes at a temperature between 0 and +5 C. The obtained ll-bromo-l3fl-ethyl-4,5-seco-A -gonene- 3,5,17-trione is not isolated from the reaction medium.

6.33 gm. of lithium carbonate and 3.16 gm. of lithium bromide are added to the reaction medium. The temperature of the reaction medium is then raised to 95 C. over a period of approximately 30 minutes. Then, the whole is agitated at 95 C. under an inert atmosphere for 3 hours. The reaction mixture is cooled to 20 C. and slowly poured into a water-ice-acetic acid mixture. The formed precipitate is extracted with methylene chloride. The methylene chloride extracts are combined, and the obtained organic solution is washed with water and dried.

To the obtained solution, 25 gm. of magnesium silicate are slowly added with agitation, and the solution is agitated for a further 15 minutes. Then, the magnesium silicate is filtered off and the solution is concentrated to dryness under reduced pressure under an atmosphere of nitrogen. The residue obtained is admixed with ethyl ether, taken to reflux, then cooled to between 0 and +5 C. The formed precipitate is filtered with suction to obtain 6.95 gm. of 13fi-ethyl-4,5-seco-A -gonadiene-3,5,17- trione, having a melting point of 128 C.

A sample of this product purified by crystallizing from methanol has a melting point of 129 to 130 C. and a specific rotation [a] =64i1.5 (c.=1% in methanol).

Analysis.-Calculated for C H O (percent), molecular weight=300.38: C, 75.96; H, 8.05. Found (percent): C, 75.8; H, 8.1.

U.V. spectrum (ethanol): mmax. at 290 mu 2:23.800.

As far as is known, 11-bromol3B-ethyl-4,5-seco-A gonene-3,5,17-trione and 13fl-ethyl-4,5-seco-A -gonadiene-3,5,17-trione are not described in the literature.

Stage B.13,8-ethyl-A -gonatriene-3,17-dione: 1 gm. of 13,B-ethyl-4,5-seco-A -gonadiene-3,5,17-trione is introduced, under an inert atmosphere, into 8 cc. of a methanolic solution of potassium hydroxide, containing 5 gm. per hundred cc. and previously freed. from oxygen by bubbling an inert gas therethrough. The reaction mixture is agitated for an hour and a half at 25 to 30 C. Then, the reaction mixture is neutralized by adding acetic acid and poured into a water-ice-mixture. The formed precipitate is filtered with suction, washed and dried to obtain 0.89 gm. of 13 8-ethyl-A -g0natriene-3,17-dione, having a melting point of C. and a specific rotation [-u] =+200i3.5 (c.=0.5% in chloroform).

A sample of this product purified by crystallization form ethanol has a melting point of C. and a specific rotation [a] =+202 (c.=0.54% in chloroform).

U.V. spectrum (ethanol). Amax. at 339 m e=29,550.

strongly active progestomimetic agent.

Example 14.Preparation of 13B-propyl-A gonatriene-3,17-dione Using the process described in Example 13, Stage A, first by subjecting the 3-methyl-3-ethoxy-4-oxa-13,8-propyl- A -gonadiene-17one, obtained in Example 9, to selective bromination in position 11, 11-.bromo-13fl-propyl-4,5-seco-A -gonene-3,5,17-trione is obtained, then by dehydrobromination with a basic agent, 13fl-propyl-4,5- seco-A -gonadiene-3,5,17-trione is obtained, F.=89 C. [a] =-595:15 (c.=0.95% in methanol).

As far as is known, 11-bromo-13p-pr0pyl-4,5 -seco- A -gonen-3,5,17-trione and 13[3-propyl-4,5-seco-A -gonadiene3,5,17-trione are not described in the literature.

Then, using the process described in Example 13, Stage B, but starting from l3fl-propyl4,5-secoA -gonadiene- 3,5,17-trione, 13p propyl-A -gonatriene-3,17-dione is obtained, F.=125 C., [a] =+250i3 (c.=1%, methanol).

This product is identical to that described in the Belgian Patent 664,389.

The preceding specific embodiments are illustrative of the practice of the invention. It is to be understood, however, that other expedients known to those skilled in the art may be employed without departing from the spirit of the invention.

We claim: 1. A 4-oxa steroid of the formula (EH 1 R" RO O wherein R and R represent lower alkyl, R and R represent a member selected from the group consisting of hydrogen, a-lOW6l alkyl and fi-lower alkyl, R and R represent a member selected from the group consisting of hydrogen, a-methyl and fi-methyl, Y represents a member selected from the group consisting of O,

OR 000m and m vm wherein R represents a member selected from the group consisting of hydrogen, lower alkyl and the acyl of an organic carboxylic acid having 1 to 1 carbon atoms, R" represents a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl and lower halo-alkynyl, and R represents a member selected from the group consisting of hydrogen and methyl.

2. The 4-oXa steroid of claim 1 wherein R is methyl, R is ethyl, R is hydrogen, R' is hydrogen, R is hydrogen, R" is hydrogen and Y is O benzoyl 3. The 4-oxa steroid of claim 1 wherein R is methyl, R' is methyl, R is hydrogen, R is hydrogen, R" is hy* drogen, R is hydrogen, and Y is O.

4. The 4-oxa steroid of claim 1 wherein R is methyl, R is ethyl, R is hydrogen, R' is hydrogen, R is hydrogen, R is hydrogen, and Y is O.

5. The 4-oxa steroid of claim 1 wherein R is ethyl, R is ethyl, R" is hydrogen, R is hydrogen, R is hydrogen, R is hydrogen, and Y is O.

6. The 4-oxa steroid of claim 1 wherein R is methyl, R is ethyl, R is hydrogen, R is hydrogen, R is hydrogen, R is hydrogen, and Y is 7. The 4-oxa steroid of claim 1 wherein R is ethyl, R is ethyl, R is hydrogen, R is hydrogen, R is hydrogen, R is hydrogen, and Y is 8. A process for the production of the 4-oxa steroid of claim 1 which comprises the steps of reacting a 3,5- dioxo-4,5-seco-A steroid of the formula wherein R represents lower alkyl, R and R represent a member selected from the group consisting of hydrogen, a-lower alkyl and fl-lower alkyl, R and R represent a member selected from the group consisting of hydrogen,

u-methyl and fl-methyl, Y represents a member selected from the group consisting of O,

{ and m vm wherein R represents a member selected from the group consisting of hydrogen, lower alkyl and the acyl of an organic carboxylic acid having 1 to 7 car-hon atoms, R represents a member selected from the group consisting of hydrogen, lower alkyl, lower a kenyl, lower alkynyl and lower haloalkynyl, and R" represents a member selected from the group consisting of hydrogen and methyl, with a lower alkyl orthoformate of the formula HC(OR wherein R represents lower alkyl, in the presence of an acid agent and recovering said 4-oxa steroid.

9. The process of claim 8 wherein said lower alkyl orthoformate is selected from the group consisting of methyl orthoformate and ethyl orthoformate.

10. The process of claim 8 wherein said acid agent is a strong acid selected from the group consisting of p-toluene sulfonic acid, methane sulfonic acid, perchloric acid and sulfuric acid.

11. The process of claim 8 wherein said reaction with said lower alkyl orthoformate is conducted in the presence of a polar organic solvent.

12. The process of claim 11 wherein said polar organic solvent is selected from the group consisting of methanol, ethanol and dioxane.

13. A process for the production of 17 8-benzoyloxy- 4,5-seco-A -estradiene 3,5 dione which comprises the steps of brominating a 4-oxa steroid of claim 1 wherein R is methyl, R' is lower alkyl, R" is hydrogen, R' is hydrogen, R is hydrogen, R is hydrogen and Y is O benzo l y COCH:

in the 11 position, dehydrobrominating the resultant llbromo-l7,B=benzoyloxy-4,5-seco-A -estrene-3,5-dione and recovering said 17B benzoyloxy-4,5-seco-A -estradiene- 3,5-dione.

14. A process for the production of 17a-ethynyl-4,5- seco A estrene-l7B-ol-3,5-dione which comprises the steps of ethynylating a 4-oxa steroid of claim 1 wherein R is methyl, R is lower alkyl, R" is hydrogen, R' is hydrogen, R is hydrogen, R is hydrogen and Y is O, by the action of an ethynylating agent in a basic medium, hydrolysing the resultant 3-methyl-3-lower alkoxy-l7aethynyl-4-oxa-A -estradiene-17 8-ol in an acid me dium and recovering said 17a-ethynyl-4,5-seco-A -estrene l7B-ol-3,5-dione.

15. A process for the production of l3fi-ethyl-l7aethynyl-4,5-seco-A -gonene-17B-ol-3,5 -dione which comprises the steps of ethynylating a 4-0Xa steroid of claim 1 wherein R is ethyl, R is lower alkyl, R" is hydrogen, R is hydrogen, R is hydrogen, R is hydrogen and Y is O, by the action of an ethynylating agent in a basic medium, hydrolysing the resultant 3 methyl-3-lower alkoxy-l3fl-ethyl-l7a-ethynyl-4 oxa-A -gonadiene- -01 in an acid medium and recovering said 13/3-ethyl- 17a-ethynyl-4,5-seco-A -gonene-17fi-ol-3,5-dione.

16. A process for the production of l3,B-ethyl-4,5-seco- A -gonadiene-3,5,17-trione which comprises the steps of brominating a 4-oxa steroid of claim 1 wherein R is ethyl, R is lower alkyl, R is hydrogen, R is hydrogen, R is hydrogen, R is hydrogen and Y is O, in the 11 position, dehydrobrominating the resultant ll-bromo-Bfi-ethyl-4,5-seco-A -gonene-3,5,l7-trione and recovering said 13 fi-ethyl-4,5-seco-A -gonadiene-3 ,5 17-trione.

17. 11-bromo-17/3-benzoyloxy 4,5 seco-A -estrene-3, S-dione.

18. 11-bromo-13,B-ethyl 4,5 seco A -gonene-3,5-17- trione.

19. 13pi-ethyl-17ot-ethynyl-4,5-seco-A gonene 1713-01- 3,5-dione.

1 7 1 8 20. 13,B-ethyl-4,5-seco-A -gonadiene-3,5,17-trione. 23. The 4-oxa steroid of claim 1 wherein R is propyl, 21. A 3-methyl-3-1ower alkoxy-lBfi-lower alkyl-4-oxa- R is ethyl, R" is hydrogen, R is hydrogen, R is hy- A ),9(r )-g nadiene of the formula drogen, R is hydrogen, and Y is O.

24. 11-bromo-135-propyl-4,5 seco A -gonene-3,5,17- R trione Z H 25. 13fl-propyl-4,5-secoA -gonad1ene-3,5,17-tr1one.

; References Cited UNITED STATES PATENTS L 10 3,085,098 4/1963 Nomine et a1. 260-586 XR 1 0 3,102,145 8/1963 Nomine et al 260-586 3,138,617 6/1964 Nomine et al 260345.2 wherein R and R' represent lower alkyl and Z represents 3150152 9/1964 Joly. et a1 260*586 a member selected from the group consisting of O 3413314 11/1968 Amlard et 260*586 XR 15 3,422,121 1/1969 Taub 260345.2 XR OH O 0 CH3 0 acyl and FOREIGN PATENTS H H H 1,366,725 6/1964 France.

where acyl represents the acyl of a carboxylic acid selected from the group consisting of benzoic acid and lower HENRY Pnmary Exammer alkanoic acid. JOHN M. FORD, Assistant Examiner 22. The compound of claim 21 wherein R is a lower alkyl selected from the group consisting of methyl, ethyl, US. Cl. X.R.

propyl and butyl and R is a lower alkyl selected from the group consisting of methyl and ethyl. 5 260 239'5? 999 2323?" NITED. TATEs PATENT OFFICE .373 NLJr: la

CERTIFICATE OF CORRECTION "um um 3 89,913 Dated March 10, 1970.

Inventor) Robert Joly, Julien Warnant and Jean Jolly It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

I ICOL, LINE '1 I 3I Correct the spelling of "methyl" (second occurrence) 2 3O Correct the spelling of "haloalkynyl" 2 6 4 After the word "member" the following words were mi tted selected from the group consisting of hydrogen and 3.7 "A 'f should read A 5 34 "HJI-seco" should read *,5-seco 8 5 Correct the spelling of "introduced" 9 &1 Correct "7a" to read 7a.

ll 27 Correct "State" to read Stage i3 39 "u.5%" should be 0.5%

14 38 "form"- should be from 15 "1 to '1". should be 1 to 7 I l7 10 Error in formula as follows:

e.v This bond should be deleted j S1gned and sealed this 24th day of November 1970. (SEAL) Attest: EDWIARD M-FLETCHER,JR- WILLIAM E. SCHUYLER, JR.

AttFStlIlg Officer Commissioner of Patents 

